The Human Cytomegalovirus (HCMV) is a highly prevalent member of the herpesvirus family infecting up to 80% of the general population. This virus is responsible for opportunistic infections in immunocompromised individuals including organ transplant recipients, cancer patients and AIDS sufferers. Clinical manifestations include disseminated disease, pneumonitis, retinitis and gastro-intestinal infections such as oesophagitis and colitis. Of particular significance are HCMV infections of neonates. This disease is the most common congenitally acquired viral infection in the world. It is estimated that 1% of newborn infants are infected and up to 10% of these are symptomatic and may experience severe complications. Mortality in this latter group approaches 30%.
All members of the herpesvirus family express a protein late in the virus life cycle which appears to function as a self assembling scaffold during the manufacture of the viral capsid. This assembly protein is present in immature B-capsids and must be processed to remove a short segment of the C-terminus in order to permit the entry of viral DNA and produce an infectious virus particle. Recently it has been shown that this processing is mediated by a protease which is encoded by the virus. The protease itself is expressed as a precursor protein which is autocatalytically cleaved at least twice (Scheme 1). Cleavage occurs near the C-terminal end of the UL80 gene product (M-site) to remove a small fragment, and also at a position located near the center of the precursor (R-site) to excise the catalytic domain (N.sub.o). Both N.sub.o and the full length protease (UL80 gene product) are catalytically active.
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HCMV protease N.sub.o shows significant sequence homology with other herpesvirus proteases. Affinity labeling experiments and site-directed mutagenesis indicate that this enzyme is a serine protease. Recent crystallographic results have shown that HCMV protease represents a novel structure of serine proteases and in fact possesses a unique catalytic triad.
While it has not been demonstrated that HCMV protease is absolutely required for viral replication, it has been shown that HSV-1 mutants lacking the analogous enzyme or expressing defective variations of it are unable to grow. The high degree of homology between the proteases of HSV and HCMV support the idea that specific inhibitors of HCMV protease would show antiviral activity and thus have therapeutic value.
EP 0,410,411 A2 discloses novel peptidase inhibitors. These peptide analogs all contain a pentafluoroethylketone at P1', however none of the peptide disclosed contain the amino acid derivatives at P2 disclosed in the present invention.
A. H. Abuelyaman et al. (Bioconjuate Chemistry, vol.5, no.5, October 1994, pp.400-405) discloses fluorescent peptide phosphonates. However, none of the peptides disclosed corresponds or leads to the peptide derivatives of the invention.
Derstine et al. (J. Am. Chem. Soc., vol. 118, no. 35, Sep. 4, 1996, pp. 8485-8486 discloses a number of peptidyl trifluoromethylketones. None of these peptides corresponds or leads to the peptide derivatives of the invention.